For understanding the invention, firstly the following technological background is important. The activation of resting T cells for the proliferation and functional differentiation firstly requires the occupation of two surface structures, so-called receptors: 1. of the antigen receptor having a different specificity from cell to cell and being necessary for the detection of antigens, e.g. viral fission products; and 2. the CD28 molecule expressed on all resting cells with the exception of a sub-group of the human CD8 T cells, said CD28 molecule naturally binding to ligands on the surface of other cells of the immune system. This is called the costimulation of the antigen-specific immune reaction by CD28. In a cell culture, these processes can be imitated by occupation of the antigen receptor and of the CD28 molecule with suitable mAbs. In the classic system of the costimulation, neither the occupation of the antigen receptor nor that of the CD28 molecule alone will lead to the T cell proliferation, the occupation of both receptors is however effective. This observation has been made with T cells of man, mouse and rat.
There are however also known CD28-specific mAbs that can initiate the T cell proliferation without costimulation. Such a superagonistic, i.e. independent from the occupation of the antigen receptor, activation of resting T lymphocytes by CD28-specific mAbs is known in the art from the document Tacke et al., Eur. J. Immunol., 1997, 27:239-247. According thereto, two types of CD28-specific monoclonal antibodies having different functional properties are described: costimulatory mAbs costimulating the activation of resting T cells only with simultaneous occupation of the antigen receptor; and superagonistic mAbs which can activate T lymphocytes of all classes in vitro and in the test animal for proliferation without occupation of the antigen receptor. Both in so far known mAbs originate from an immunization with cells, on which rat CD28 is expressed, and are obtainable by different selections directed to their respective properties.
From the document DE-197 22 888 it is known in the art that superagonistic mAbs are capable to effect an immune deviation TH1 to TH2 and are therefore suitable for use against adjuvant arthritis. TH1 and TH2 cells are CD4-expressing T cells. TH1 cells are also called pro-inflammatory T helper cells and secern the cytokines IL-2, TNF and IFN-γ. TH2 cells support the activation of B cells and secern the cytokines IL-4, IL-5 and IL-10. The differentiation of CD4 T cells from the above functionally different sub-groups is not only controlled by the available cytokines, but it is also modulated by costimulation over CD28. CD28-deficient mice show normal TH1, but reduced TH2-dependent answers and the cytokine profile of TCR transgenic CD4 cells is displaced by CD28 ligation in the direction TH2. On the other hand, a strong TCR signal will prevent CD28-mediated TH2 differentiation.
From the primary literature summarized in the document K. J. Maloy et al., Nature Immunology, vol. 2, No. 9, pages 816 ff., 2001, it is known that regulatory T cells are important for autoimmune reactions. For instance in experimental animal models of the multiple sclerosis, of the type 1 diabetes and of inflammatory intestinal diseases, the capability of these cells to suppress the respective symptoms was shown.
The Guillain-Barré syndrome is an acute autoimmune-inflammatory disease of the peripheral human nervous system. The incidence of GBS is 1 to 2 per 100,000 inhabitants. The chronic form is the chronic demyelinating polyneuropathy (CDP). The incidence of CDP is 10 to 20 per 100,000 inhabitants. mAbs or related substances for the prevention and/or treatment of these diseases are not known.
Technical Object of the Invention
The invention is based on the technical object to specify a pharmaceutical composition, by means of which regulatory T cells can be stimulated and which is particularly suited for the prevention and/or treatment of the multiple sclerosis, type 1 diabetes, inflammatory intestinal diseases, GBS and/or CDP.